The main objective of the proposed research is to investigate the functional characteristics of the voltage-dependent ion channels in normal and denervated mammalian skeletal muscle. The singnificance of this investigation will be in the elucidation of the modecular mechanisms of excitation in normal muscle and the alterations of these mechanisms, which take place after the removal of the regulatory influence of the motor nerve and lead to the development of spontaneous repetitive activity (fibrillation potientials). The proposed study will be use the most direct electrophysiological technique the voltage clamp, to study ion conductances in rabbit skeletal muscle membrane. Three lines of investigation will be followed: 1) the time and voltage dependent parameters of sodium, potassium and calcium conductances will be measured and analyzed according to a modified Hodgkin-Huxley model: 2) denervation-induced alterations of these conductances will be analyzed to determine their role in spontaneous repetitive activity; and 3) the ionic mechanisms of action of pharmacological agents known to either enhance (e.g., epinephrine and isoproterinol) or inhibit (e.g., ouabain, tetrodotoxin and Mn++) fibrillation, will be studied in voltage-clamped normal and denervated muscle in order to distinguish between different hypotheses of the origin of fibrillation potentials. In particular, we will try to determin whether spontaneous activity is due to an alteration of either one or more ion channels (sodium, potassium of calcium), or athe Na-K pump. Since the denervation-induced changes in orverall muscle membrane exitability appear to stem from alterations in either the furnction ora the distribution of membrane proteins which mediate ion transport, the elucidation of the specific effects of denervation using voltage clamp technique will be an important step toward understanding the long-term regulation of ionic channels in excitable membranes.